Suppression of protein synthesis in the brain following an ischemic insult has been thought to occur because of inhibition of translation initiation. All eukaryotic mRNAs, with the exception of heat-shock transcripts, require the activity of eukaryotic initiation factor (eIF) 4E for formation of the translation initiation complex, and eIF-4E availability is rate-limiting. The response of brain eIF-4E concentration and phosphorylation following decapitation ischemia was studied in rat brain homogenates after electrophoresis and western blotting with antibodies against eIF-4E and phosphoserine, respectively. There was no change in level of eIF-4E after 5 min of ischemia (p = 0.82 vs. time 0), but it had decreased 32 (p = 0.01) and 57% (p = 0.006) after 10 and 20 min of ischemia, respectively. There was no loss of serine phosphorylation on eIF-4E beyond signal loss observed due to degradation of the protein itself (p = 0.31). In vitro exposure of eIF-4E to activated mu-calpain resulted in a 50% loss in 10 min of eIF-4E on western blots. If active eIF-4E is required for translation of its own mRNA, degradation of this protein during ischemia, possibly by activated mu-calpain, could be a direct mechanism of irreversible neuronal injury, and the rate of proteolysis of eIF-4E could place an upper time limit on the maximal duration of global brain ischemia compatible with neurologic recovery.